FOLR1 ( Folate receptor alpha )

MIRV as ≥3L treatment in heavily pretreated recurrent FRα-positive PSOC demonstrated notable efficacy and tolerable safety, including among those with prior PD on or within 30 days of PARPi. (Funding, ImmunoGen, Inc; NCT05041257).

We identified a gene expression signature correlated to high FRα expression and OC prognosis, which may be used to refine therapeutic strategies targeting FRα in OC. These findings warrant validation in larger cohorts.

We summarize the mechanisms of the action of various therapeutic strategies based on FRα, including MABs (monoclonal antibodies), ADCs (antibody-drug conjugates), FDCs (folate-drug conjugates), SMDCs (small molecule-drug conjugates), vaccines, and CAR-T (chimeric antigen receptor T) cells, and present the most significant clinical trials of some FRα-based drugs. Furthermore, we discuss the pros and cons of different FR-based therapies, highlighting mirvetuximab soravtansine (MIRV) as the currently most promising EOC-targeting drug.

Our validation strategy highlights that assays comprehensively characterizing CAR functionality and binding specificity complement each other. Thereby, critical specificity considerations can be addressed early in the development process to overcome current limitations for future CAR T cell therapies.

P1, N=423, Recruiting, ImmunoGen, Inc. | N=227 --> 423

P2, N=90, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P3, N=453, Completed, ImmunoGen, Inc. | Active, not recruiting --> Completed

This report emphasizes the crucial role of meticulous sampling and histopathologic examination of the fallopian tube, including the fimbriae, in all salpingectomy specimens. Furthermore, the case highlights the broad spectrum of morphologies encountered in HGSC, including mucinous differentiation. HGSC should be in the differential diagnosis when encountering mucin-producing high-grade carcinoma.

FRα-targeting ADCs, including MIRV, demonstrated definite efficacy and good safety as novel choices for second-line and beyond treatment of advanced or recurrent ovarian cancer. Patients with high FRα expression showed ORR and PFS benefits similar to those in the overall cohort.

P2, N=18, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Aug 2028 --> May 2027 | Trial primary completion date: Aug 2025 --> Jun 2024

ADCs offer the opportunity for a more effective and personalized treatment approach for gynecologic cancer patients. Side effects must be closely monitored, and preventive measures must be followed to maximize benefit and minimize toxicity. A better understanding of the role of target proteins as biomarkers to predict response to ADCs will be critical for successful clinical implementation of ADCs and further research in this area is necessary.

As demonstrated among 682 participants, the safety profile of MIRV is well tolerated and consists primarily of low-grade gastrointestinal, fatigue, headache, peripheral neuropathy, and resolvable ocular adverse events.

P2, N=136, Active, not recruiting, AGO Research GmbH | Recruiting --> Active, not recruiting

P=N/A, N=272, Not yet recruiting, University of British Columbia

Due to the very limited number of NAb-positive individuals, no conclusions could be drawn on the effect of NAb on efficacy. Both the validation tests and the data from the MIRV clinical studies demonstrated that these assays were suitable and reliable for the detection of MIRV ADAs and NAbs. These validated assays will continue to be used to monitor MIRV immunogenicity in future clinical trials.

This study confirmed that IFN-γ and TNF-α secreted by αFR-CAR-engineered NK cells can synergistically induce high expression of CXCL10 in ovarian cancer cells and constructed self-driving αFR-CAR-engineered NK cells that can break through migration barriers based on CXCL10, which may provide a new therapeutic weapon for ovarian cancer.

It encapsulates the advancements and clinical trials of novel ADCs that target specific antigens such as Folate Receptor alpha (FRα), MUC16, NaPi2b, Mesothelin, Dipeptidase 3(DPEP3), and human epidermal growth factor receptor 2 (HER2), as well as tissue factor, highlighting their potential anti-tumor efficacy and used in combination with other therapies. The ADCs landscape in ovarian cancer therapeutics is swiftly evolving, promising more potent and efficacious treatment avenues.

Though less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting.

97.5% had prior taxanes, 81% prior poly (ADP-ribose) polymerase inhibitors (PARPi) [74.7% of whom progressed while on PARPi], 64.6% prior bevacizumab, 98.8% had 2+ prior lines of therapy, and BRCA status was 27.8% positive, 72.2% negative. MIRV demonstrated notable efficacy in this heavily pretreated PSOC population, including among those who may have PARPi resistance. MIRV continues to demonstrate a differentiated safety profile consisting primarily of low-grade neurosensory, GI, and resolvable ocular AEs. These data position MIRV to become a novel treatment option for patients in ≥3L PSOC with FRα positive expression.

Introduction Mirvetuximab soravtansine-gynx (MIRV) is an antibody-drug conjugate that binds to folate receptor alpha and delivers a microtubule inhibitor payload...Median PFS did not significantly differ based on number of prior treatment lines (for 1-3 versus >3 lines, P = 0.3) or prior PARP inhibitor ( P = 0.9) or bevacizumab ( P = 0.4) use...Conclusion/Implications MIRV confers meaningful PFS benefit for a subset of individuals. Biomarkers of response and resistance are urgently needed to optimize patient selection for treatment.

P1, N=86, Active, not recruiting, Shattuck Labs, Inc. | Trial completion date: Apr 2025 --> Nov 2024

Given that folate is essential for key cellular processes, including DNA/RNA synthesis, methylation, nitric oxide, and neurotransmitter synthesis, we conclude that ageing or some form of trauma in life can lead to CSF accumulation and ventricular enlargement and result in a specific folate imbalance/deficiency associated with the specific neurological condition. We believe that addressing cerebral folate imbalance may therefore alleviate many of the underlying deficits and symptoms in these conditions.

Additionally, we present an aggregate of ongoing clinical trials investigating the available treatment options targeting such alterations, in addition to their current recruitment status and preliminary efficacy data. These advancements may guide further research endeavors and inform future treatment strategies to improve the management of and transform outcomes for patients with advanced NSCLC.

Furthermore, we demonstrate that detecting distinct colocalized biomarkers on the surface of EVs significantly improves discrimination performance relative to single biomarker measurements. Using this approach, we observe promising discrimination of high-grade serous ovarian cancer versus benign ovarian masses and healthy women in a proof-of-concept clinical study.

Overall, while [18F]fluoro-PEG-folate was well-tolerated, its clinical utility in the preoperative assessment of the extent of disease in EOC was limited. This highlights the need for further research in developing targeted imaging agents for optimal detection of EOC metastases.

P1, N=12, Not yet recruiting, Fred Hutchinson Cancer Center

The trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.

P=N/A, N=50, Recruiting, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital Hainan Hospital; Hangzhou ZhongMei Huadong Pharmaceutical Co., Ltd.

Our data highlight the need for caution in antibody selection when developing immunohistochemical-based assays, as some FRα antibodies failed to cleanly and specifically identify FRα expression. We identified two antibodies appropriate for further investigation; however, as developed, both stain more intensely than the FDAapproved test and may, therefore, over-select patients for treatment with FRα-targeted therapies intended for use with the FDA-approved companion diagnostic. From these data, we advise the use of the FDAapproved assay for patient selection.

FOLR1 expression was upregulated by VPA, apicidin, and trichostatin A, but downregulated by MS-275 after 24 h treatment. By contrast, HDAC inhibitors exert different regulatory effects on folate carriers. Moreover, HDAC1/2 inhibition may be a potential mechanism involved in altering FOLR1 and SLC46A1 levels.

Our study highlighted the significant association of BPA with OS biology, particularly in its potential role in modulating the tumor immune microenvironment. We offered a fresh insight into the influence of BPA on cancer development, thus providing valuable insights for future clinical interventions and treatment strategies.

P2/3, N=600, Recruiting, Sutro Biopharma, Inc. | Trial completion date: Feb 2026 --> Feb 2028 | Trial primary completion date: Sep 2025 --> Aug 2027

Cell block samples show significantly less staining for FOLR1 compared to tissue sections from the same patients. Pathologists should be aware of this limitation.

P1, N=170, Recruiting, Coherent Biopharma (Suzhou) Co., Ltd. | Trial primary completion date: Dec 2023 --> Oct 2024

P2, N=50, Recruiting, Alessandro Santin

No abstract available

P1, N=86, Active, not recruiting, Shattuck Labs, Inc. | Trial primary completion date: Jul 2024 --> Dec 2024

P1, N=227, Recruiting, ImmunoGen, Inc. | Trial primary completion date: Jun 2024 --> Dec 2024

P3, N=453, Active, not recruiting, ImmunoGen, Inc. | Trial completion date: Apr 2024 --> Aug 2024

In FRα-high PSOC, MIRV plus bevacizumab previously showed promising efficacy (objective response rate, 69% [95% CI: 41-89]; median progression-free survival, 13.3 months [95% CI: 8.3-18.3]; median duration of response, 12.9 months [95% CI: 6.5-15.7]) and safety. The Phase III randomized GLORIOSA trial will evaluate MIRV plus bevacizumab vs. bevacizumab alone as maintenance therapy in patients with FRα-high PSOC who did not have disease progression following second-line platinum-based doublet chemotherapy plus bevacizumab.Clinical Trial Registration: ClinicalTrials.gov ID: NCT05445778; GOG.org ID: GOG-3078; ENGOT.ESGO.org ID: ENGOT-ov76.

Mirvetuximab soravtansine-gynx (MIRV) is a folate receptor alpha (FRα) directed antibody and microtubule inhibitor that is approved for patients with FRα positive platinum resistant recurrent epithelial ovarian cancer...It is suspected that most paclitaxel reactions are due to the cremophor solvent rather than paclitaxel itself; however, cross reactivity with docetaxel which is suspended in a polysorbate solution can also occur...MIRV is also suspended in polysorbate and has a similar mechanism to taxanes, therefore it was unknown if a patient with a prior grade 5 reaction to paclitaxel would also have a reaction to MIRV. Though this is one case, patients with a history of severe hypersensitivity to paclitaxel and meet the criteria for MIRV could be treated with MIRV with careful monitoring.

We focused particularly on the most promising antibody-drug conjugate targets in endometrial cancer under clinical investigation, such as human epidermal growth factor receptor 2 (HER2), folate receptor alpha (FRα), trophoblast cell-surface antigen-2 (TROP2), and B7-H4. We also briefly comment on the challenges, including the emergence of resistance mechanisms, and future development directions (especially agents targeting multiple antigens, combinatorial strategies, and sequential use of agents targeting the same antigen but using different payloads) in antibody-drug conjugate therapy for endometrial cancer.